The goal of the proposed planning grant and study is to reduce the use of unnecessary antimicrobials in critically ill patients by demonstrating that withholding antibiotics until objective data returns is safe and effective in patients suspected of having an infection without septic shock. Based on a prior pilot study, two strategies for starting antimicrobial agents in patients in the ICU will be compared: Starting antibiotics as soon as an infection is suspected or waiting until early culture data returns confirming an infection. The specific aims are to 1) Determine the infection-related mortality in patients treated with each strategy, 2) Determine the rates of infection, total number of days of antimicrobial use, and rates of secondary infections with multidrug resistant organisms, 3) Determine the utility of a clinico- metabolomic models to predict which septic patients actually harbor infection and the mortality in infected patients, identifying high-risk patients that could benefit from aggressive antimicrobil therapy. The proposal is for a six-center, cluster-randomized, protocol crossover, pragmatic, unblinded, comparative effectiveness trial of the equivalence of two strategies in the management of critically ill surgical patients suspected of having a new-onset, ICU-acquired infection. An estimated 8,500 patients treated in ICUs will be followed with a baseline infection-related mortality of 15%. Power analysis suggests that this sample size will be adequate to demonstrate equivalence between the two strategies in terms of infection-related mortality, and sufficient to show significant decreases in antimicrobial usage in the conservative treatment group. In addition, a subset of patients will have plasma fatty acid metabolites analyzed to prospectively identify patients at particularly high risk of infection and death. If withholding antimicrobials until objective evidence of infection returns can be performed without worsening outcomes, a beneficial reduction of antimicrobial use of at least 25% may be possible among highly vulnerable, critically ill patients.